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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
  • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
  • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups

Definitions

• the present invention relates to a process for the preparation of 2,4-diamino-3-hydroxybutyric acid derivatives.
• 2 (S), 4-diamino-3 (S) -hydroxybutyric make this latter molecule particularly attractive for use in the pharmaceutical industry, agrochemical or materials science.
• the 2 (S), 4-diamino-3 (S) and hydroxybutyric protected derivative thereof, such as acid 2 (S), 4-diamino-3 (S) -hydroxybutyriques whose primary amine functional groups and optionally hydroxyl function are protected, can thus be useful as a building block in the synthesis of various molecules, in particular in the synthesis of new peptides. It then appears desirable to be able to synthesize these compounds on a large scale and at a lower cost.
• the proposed synthesis route comprises, in penultimate step, a chiral separation leading to significant losses in product. Moreover, this synthesis performed on a small scale, n 'has led that a few milligrams of the product of interest "2,4-diamino-3-hydroxybutyric acid protected" with an overall molar yield of no more than 6.4%. Such a synthesis can not be realistically implemented on a large scale.
• This method can, however, be applied on a large scale because of the low stereoselectivity of the epoxidation step and the large number of steps required to access the compound of interest (8 steps).
• the present invention relates to a process for the synthesis of compounds of formula (I) below:
• R 1 and R 2 denote, independently of one another, protective groups of the amine functions
• R 3 denotes a hydrogen or a group protecting the amine functions and R 4 denotes a hydrogen or a group protecting the hydroxyl functions, or R 3 and R 4 together form a group chosen from -C (CH 3 ) 2 -, -CH (CH 3 ) -, -C ((CH 2 ) 4 ) -, -C ((CH 2 ) 5 ) -, -CH (C 6 H 5 ) -, -CH ((p-OCH 3 ) C 6 H 4 ) -, -CH ((m, p-OCH 3 ) C 6 H 3 ) - and -C (O) -:
• R 5 denotes a hydrogen, an alkyl radical, an aryl radical or a heteroaryl radical:
• the present invention also relates to a synthesis method of 2,4-diamino-3 (S) -hydroxycarboxylique from 5-hydroxyectoine.
• FIG. 1 represents the synthesis scheme of the four diastereoisomers derived from 2,4-diamino-3-hydroxybutyric acid whose primary amino and hydroxyl functions are protected according to the prior art.
• the inventors have developed a protected derivatives process for preparing the 2 (S), 4-diamino-3 (S) -hydroxy butyric acid, from the acid (4S, 5S) -5-hydroxy- 2-methyl-1, 4,5,6-tetrahydropyrimidine-4-carboxylic acid (2), more commonly referred to as "5-hydroxyectoin”:
• protected derivatives of 2 (S), 4-diamino-3 (S) -hydroxy butyric is designated in the description of the present invention a 2 (S), 4-diamino-3 (S) hydroxy-butyric whose primary amine functions, and optionally the hydroxyl function, are protected by means of suitable protective groups.
• Protected derivatives of the acid 2 (S), 4- diamino-3 (S) -hydroxy butyric acid may be N-substituted in position 2.
• the protected derivatives of 2 (S), 4-diamino-3 (S) -hydroxy butyric acid are represented by the formula (I) :
• R 2 denote, independently one of the other protective groups for amino functions
• R 3 denotes a hydrogen or a group protecting the amine functions and R 4 denotes a hydrogen or a group protecting the hydroxyl functions, or R 3 and R 4 together form a group chosen from -C (CH 3 ) 2 -, -CH (CH 3 ) -, -C ((CH 2 ) 4 ) -, -C ((CH 2 ) 5 ) -. -CH (C 6 H 5 ) -, -CH ((p-OCH 3 ) CeH 4 ) -, -CH ((m, p-OCH 3 ) C 6 H 3 ) - and -C (O) -;
• R 5 denotes a hydrogen, an alkyl radical. an aryl radical or a heteroaryl radical.
• i and R 2 may be different or the same.
• Ri and R 2 are preferably different.
• the protective groups of amino functions, primary or secondary, are well known to the skilled person. These groups protect the amino functions of the undesirable reactions. For example, a chemical reaction can be carried out selectively at another reactive site that is unprotected him. Protecting groups of the amino functions can be as described in "Protective Groups In Organic Synthesis” (John Wiley & Sons, New York (1981)) and Harrison et al.
• Amino functional groups include carbamates, amides, amino acetal derivatives, N-benzyl derivatives, imine derivatives, and the like. derivatives N-heteroatom.
• R and R 2 may be chosen from the acetyl, benzoyl, pivaloyl, phenylsulfonyl, benzyl (Bn), t butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, trichloroethoxycarbonyl (TROC), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, benzyl carbamates (substituted or unsubstituted) and the like.
• R 1 is a Boc group and R 2 is a Fmoc group.
• the protecting groups of the hydroxyl functions are well known to the skilled person. These groups protect the hydroxyl functions of the undesirable reactions.
• the protective groups of the hydroxyl functions may be as described in Greene, "Protective Groups In Organic Synthesis", (John Wiley & Sons, New York (1981)) and Harrison et al.
• the protecting groups of the hydroxyl functions include ethers or esters of methyl or substituted or unsubstituted alkyl, for example methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, t-butyl, benzyl and triphenylmethyl, benzyl ethers (substituted or unsubstituted), tetrahydropyranyl ethers, allyl ethers, substituted ethyl ethers, for example 2,2,2-trichloroethyl, silyl ethers or alkylsilyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl, heterocycle ethers and esters prepared by reacting the hydroxyl
• alkyl denotes linear or branched saturated hydrocarbon chains comprising from 1 to 20 carbon atoms, preferably from 1 to 12 atoms or even from 1 to 6 carbon atoms.
• alkyl radical include methyl, ethyl, n-propyl, isopropyl, n-butyl, / 'so-butyl, sec-butyl, and tert-butyl.
• aryl means an aromatic monocycle or a polycyclic system comprising at least one aromatic ring fused to at least one other ring which may be aromatic or nonaromatic.
• the aryl radicals can comprise from 5 to 10 carbon atoms.
• the aryl radical may be phenyl.
• heteroaryl refers to an aryl as defined above in which one or more carbon atoms is / are replaced by a heteroatom, such as a nitrogen, sulfur or oxygen atom.
• the letters “p” and “m” designate respectively the “para” and “meta” positions of a phenyl radical.
• the letters “p, m” indicate that the phenyl radical is substituted in the para and meta positions. Unless otherwise indicated, the reactions described below are carried out at ambient pressure and the reaction yields indicated are molar yields.
• room temperature refers to a temperature ranging from 18 ° C to
• the synthetic route does not require chiral synthesis because the chiral centers are present in the starting reagent;
• R 2 denote, independently one of the other protective groups for amino functions
• R 3 denotes a hydrogen or a group protecting the amine functions and R 4 denotes a hydrogen or a group protecting the hydroxyl functions, or R 3 and R 4 together form a group chosen from -C (CH 3 ) 2 -, -CH (CH 3 ) -, -C ((CH 2 ) 4 ) -, -C ((CH 2 ) 5 ) -, -CH (C 6 H 5 ) -, -CH ((p-OCH 3 ) C 6 H 4 ) -. -CH ((mp-OCH 3 ) C 6 H 3 ) - and -C (O) -;
• R 5 denotes a hydrogen, an alkyl radical, an aryl radical or a heteroaryl radical
• step (b) regioselective protection with an R- ⁇ group of the primary amine function at the 4-position of the 2,4-diamino-3 (S) -hydroxybutyric acid obtained in step (a);
• step (d) optionally protecting the hydroxyl function at position 3 with an R 4 group and / or protecting the secondary amine in position 4 with an R 3 group of the compound obtained in step (c) or protecting the hydroxyl functional groups in position 3 and secondary amine in position 4 to obtain a compound of formula (I) in which R 3 and R 4 together form a group selected from -C (CH 3 ) 2 -, -CH (CH 3 ) -, -C ( (CH?) 4) -, -C ((CH?) 5) -, -CH (C 6 H 5) -, -CH ((p-OCH 3) C 6 H 4) -, -CH ((m p-OCH 3 ) C 6 H 3 ) - and -C (O) -;
• step (e) optionally N-alkylation or N-arylation at the 2-position of the compound obtained in step (d) to obtain a compound of formula (I) wherein R 5 is an alkyl group or an aryl or heteroaryl group; (f) recovering the compound of formula (I) obtained in step (c) or, where appropriate, in step (d) or (e).
• Steps (a), (b), (c), (d) and (e) may be as described in detail below.
• 2,4-Diamino-3 (S) -hydroxybutyric acid is typically obtained with a diastereomeric (2S, 3S: 2R, 3S) ratio of at least 70:30.
• the conversion is quantitative (LC-MS analysis).
• the basic hydrolysis of the hydroxyectoin can be carried out by heating at a temperature greater than or equal to 50 ° C for at least 3.5 hours in the presence of at least one molar equivalent, preferably from one to two equivalents, of a strong base, such as sodium hydroxide, potassium hydroxide, lithium hydroxide or barium hydroxide.
• a strong base such as sodium hydroxide, potassium hydroxide, lithium hydroxide or barium hydroxide.
• the hydrolysis is carried out in the presence of two molar equivalents of sodium hydroxide at a temperature of 50 ° C for five hours.
• Basic hydrolysis is typically carried out in exclusively aqueous medium.
• Basic hydrolysis under such conditions leads to the opening of the hydroxyectoine ring producing a monoacetyl derivative.
• the intermediate obtained is then deacetylated by acid hydrolysis, for example in the presence of hydrochloric acid, sulfuric acid, nitric acid, iodohydric acid, hydrofluoric acid, perchloric acid or hydrobromic acid, by heating at a temperature of at least 95 ° C for at least 1 hour.
• the acid hydrolysis can be conducted in one or more steps, depending In this way, if necessary, a first acid hydrolysis can be performed, followed by removal of the water and then a second hydrolysis.
• Deacetylation is preferably carried out in the presence of 12 N concentrated hydrochloric acid at a temperature of at least 100 ° C for 1 hour.
• the deacetylation is typically carried out directly on the crude reaction product obtained at the end of the basic hydrolysis step.
• Basic hydrolysis carried out in the presence of two molar equivalents of sodium hydroxide at a temperature of 50 ° C for five hours, followed by deacetylation by acid hydrolysis in the presence of 12 N concentrated hydrochloric acid at a temperature of at least 100 ° C for 1 hour leads to 2 (S), 4-diamino-3 (S) -hydroxy butyric acid with a diastereomeric (2S, 3S: 2R, 3S) ratio of 70:30.
• the basic hydrolysis of hydroxyectoin (opening of the hydroxyectoin ring by basic hydrolysis) and deacetylation can be carried out in a single step by heating at a temperature greater than or equal to 85 ° C for at least 18 hours. in the presence of at least seven molar equivalents of a strong base.
• the strong bases may be as described above.
• the reaction is typically carried out in exclusively aqueous medium.
• the present invention also relates to a process for synthesizing 2,4-diamino-3 (S) -hydroxycarboxylic acid from 5-hydroxyectoin.
• the process comprises basic hydrolysis of hydroxyectoin (opening of the hydroxyectoin ring by basic hydrolysis) and deacetylation to yield 2,4-diamino-3 (S) -hydroxybutyric acid.
• the basic hydrolysis and deacetylation are as described above.
• 2,4-Diamino-3 (S) -hydroxycarboxylic acid is obtained as a mixture of diastereoisomers: 2 (S), 4-diamino-3 (S) -hydroxycarboxylic acid and 2 (R) -acid , 4-diamino-3 (S) -hydroxycarboxylique.
• the compounds obtained can be separated by methods well known to those skilled in the art, such as by chromatography. Reposelective protection of the primary amine function in position 4 (step (b))
• the regioselective protection of the primary amine function at the 4-position of the 2,4-diamino-3 (S) -hydroxybutyric acid (3) obtained in step (a) can be carried out in various suitable ways. It leads to compounds of formula (I) in which R 2 , R 3 , R 4 and R 5 represent hydrogen atoms and R 1 represents a protective group of amino functions, that is to say
• R 1 is as defined above.
• regioselective protection can be achieved in three steps.
• a copper complex is prepared by bringing the 2,4-diamino-3 (S) -hydroxybutyric acid obtained in step (a) with a copper complex, such as CuSO 4 . 5H 2 O, CuSO 4 , Cu 2 (OH) 2 CO 3 , Cu (OAc) 2 or CuCO 3 .
• a copper complex such as CuSO 4 . 5H 2 O, CuSO 4 , Cu 2 (OH) 2 CO 3 , Cu (OAc) 2 or CuCO 3 .
• the reaction is typically carried out in water at reflux or ambient temperature.
• the complexation makes it possible simultaneously to protect the carbonyl function and the primary amine function at the 2-position of the compound obtained in step (a).
• a copper complex is prepared using copper sulfate pentahydrate.
• the primary amine function in position 4 is protected by means of a protective group R- ⁇ adapted.
• the primary amine function at the 4-position may be protected by a t-butoxycarbonyl (Boc) or benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, trichloroethoxycarbonyl (TROC), allyloxycarbonyl (Alloc), 9-Fluorenylmethyloxycarbonyl (Fmoc). Protection by such protecting groups can be achieved under conditions well known to those skilled in the art.
• the reaction is carried out at room temperature.
• Ri is a Boc group.
• a protecting group Boc is preferably carried out by reacting the compound obtained after complexation with copper with an anhydrous formula of (Boc) 2 0 or C0 2 tBu N 3 / MgO in a solvent, such as acetone, water, methanol, ethanol, THF or dioxane.
• a solvent such as acetone, water, methanol, ethanol, THF or dioxane.
• the decomplexation of the copper can be carried out by reaction with 8-quinolinol or commercially available decomplexing resins (Chelex 100 for example) or EDTA salts. Typically, the reaction is carried out at room temperature. Preferably, the decomplexation of the copper is carried out with 8-quinolinol, typically in water.
• This third step of decomplexing copper is optional. Thus, it is also possible to use in the rest of the process directly the copper complex obtained.
• the 2,4-diamino-3-hydroxybutyric acid protected at position 4 of (2S, 3S) configuration, or its copper complex is obtained at the end of these steps with a diastereomeric purity greater than 90. %, preferably greater than 95%.
• the regioselective protection of the primary amine function at the 4-position of the 2,4-diamino-3 (S) -hydroxybutyric acid obtained in step (a) can be carried out by complexation of the boron atom. 9-BBN by the amino function in position 2 and the acid function. This complexation allows the temporary protection of the amine function in position 2.
• the primary amine function in position 4 is protected by means of a protective group Boc.
• the reaction conditions of the protective reaction are well known to those skilled in the art. Typically, the reaction is carried out at room temperature.
• the primary amine function in position 4 is protected by means of a Boc protecting group by reaction of the complex obtained, under basic conditions, with Boc 2 0.
• the boron is then decomplexed in the presence of ethylene diamine.
• the regioselective protection of the primary amine function at the 4-position of 2,4-diamino-3 (S) -hydroxybutyric acid obtained in step (a) can be achieved by reaction with sodium hydroxide and (Boc) 2 0 or C0 2 tBu N 3 or with 1H-benzotriazole, DMAP and Boc 2 0 2 or PhOC0 tBu, typically at room temperature.
• R- ⁇ and R 2 are as defined above.
• the group R 2 may be a t-butoxycarbonyl (Boc), benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, trichloroethoxycarbonyl (TROC), allyloxycarbonyl (Alloc) or 9-fluorenylmethyloxycarbonyl (Fmoc) group.
• the protection of the primary amine function in the 2-position is preferably carried out by a 9-fluorenyl-methoxycarbonyl (Fmoc) group.
• Fmoc 9-fluorenyl-methoxycarbonyl
• the introduction of a Fmoc group can be carried out under conditions well known to those skilled in the art, for example, by reaction of the product obtained in step (b) with 9-fluorenyl-methoxycarbonyl hydroxy succinimide (FmocOSu) in the presence of a solvent such as dioxane, typically at room temperature.
• the compound of formula (Ib) obtained at the end of this step can be recovered. It can be purified by chromatography on a silica column with a heptane / ethyl acetate gradient of 100: 0 to 0: 100 (volume: volume). The product is then obtained with a yield of 30% on the first four stages.
• the compound of formula (Ib) obtained at the end of this step (c) may optionally be subjected to steps (d) and optionally (e) described below, before or after purification.
• step (d)) The protection of the hydroxyl functional groups in the 3-position and the secondary amine in the 4-position can be carried out by means of suitable protective groups leading to the compounds of formula (I) in which R 1 and R 2 are as described above, R 5 denotes a hydrogen, R 3 denotes a hydrogen or a group protecting the amino functions and F denotes a hydrogen or a group protecting the hydroxyl functions or R 3 and R 4 together form a group selected from -C (CH 3 ) 2 , -CH (CH 3 ) -, -C ((CH 2 ) 4 ) -, -C ((CH 2 ) 5 ) ⁇ , -CH (C 6 H 5 ) -, -CH ((p-OCH 3 ) C 6 H 4 ) -, -CH ((m, p-OCH 3 ) C 6 H 3 ) - and -C (O
• the protection of the hydroxyl function in position 3 and the secondary amine function in position 4 is performed by means of an isopropylidene leading to the compounds of formula (I) as described above wherein R 3 and R 4 together form a -C (CH 3 ) - group, or to the compounds of formula (Id) below:
• R 1 and R 2 are as described above.
• reaction between the compound of formula (Ib) obtained at the end of step (c) and 2,2'-dimethoxypropane is typically carried out in dichloromethane in the presence of BF 3 .OEt 2 , preferably at 0.degree. ° C.
• the compound is obtained at the end of this step with a diastereomeric purity greater than 90%, preferably greater than 95%.
• the yield of the reaction is 70%.
• the compound obtained can then be purified by recrystallization.
• a / -substituted derivatives can be carried out in three steps from the compound obtained in step (d): esterification of the acid function, N-substitution (N-alkylation or N-arylation) of the free carbamate function and chemo-selective saponification of the ester function in the presence of the Fmoc group.
• the reactions are carried out under conditions well known to those skilled in the art.
• the first esterification step takes place in the presence of an alcohol and a coupling agent.
• the N-substitution on the free carbamate function can be of two kinds:
• an alkylating agent RX such as an alkyl halide, an alkyl sulphonate, optionally a base (different from a secondary amine) and optionally a solvent (different from a secondary amine and an alcohol).
• metals halides, sulphonate, diazonium, etc.
• a catalyst system a metal optionally with a ligand, optionally a base and optionally a solvent.
• the saponification of the ester function in the presence of the Fmoc protecting group is carried out selectively, preferably in the presence of NaOH and CaCl 2 , or in the presence of Lil or Me 3 SnOH.
• step (d) and optionally (e) are recovered. They can be purified by methods well known to those skilled in the art.
• protected derivatives of 2,4-diamino-3-hydroxy butyric acid is prepared by the following synthetic scheme:
• the desired product (1) was obtained with an overall yield of about 21% and a chiral purity of greater than 95%.
• the pale yellow solid obtained in the preceding stage is dissolved in 60 mL of water.
• the solution obtained is cooled to 0 ° C.
• Sodium bicarbonate (2.0 equiv., 10.6 g, 126.4 mmol) is then added portionwise.
• a solution of CuSC 5 H 2 O (0.5 equiv., 7.9 g, 31.6 mmol) in water (20 mL) is added dropwise to the previous solution.
• the green solution obtained is stirred at room temperature for 18 hours.
• the solution is then cooled to 0 ° C.
• Sodium bicarbonate 2.0 equiv., 10.6 g, 126.4 mmol
• the compound is purified by chromatography on a silica column (heptane / ethyl acetate 100: 0 to 0: 100).
• Compound 5 is obtained in the form of a white solid (8.6 g, purity: 95% by LC-MS).
• Compound 5 is obtained with an overall yield of 30% over 4 stages.
• the system was heated from 25 to 110 ° C (in 25 minutes) then to 110 ° C for 30 minutes and then cooled to room temperature for 4 hours.
• a solution of Boc 2 0 (2.0 eq., 320 mmol, 52.0 g) in dioxane (275 mL) was added and the reaction was stirred at room temperature for 70 hours.
• a solution of Boc 2 0 (0.5 eq., 80 mmol, 13.0 g) in dioxane (60 mL) was added slowly and the mixture stirred at room temperature for 24 hours. The suspension obtained was filtered.
• the aqueous phase was extracted with ethyl acetate (2 * 200 mL).
• the organic phases were combined, washed with 0.1 N aqueous HCl solution (200 mL) and saturated aqueous NaCl solution (200 mL), dried over MgSO 4 , filtered and concentrated.
• the pale yellow oil obtained was dissolved in diethyl ether (100 mL) and the solution was cooled with an ice bath and then hexane (400 mL) was added. When adding hexane, the formation of solids was observed. At the end of the addition, the presence of a sticky solid at the bottom of the flask was observed.
• HMBC HMBC and HSQC

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